Cancer is one of the most life threatening diseases in which cells in a part of the body experience out-of-control growth. According to the latest data from American Cancer Society, cancer is the second leading cause of death in the United States (second only to heart disease) and claimed more than 550,000 lives in 2007. In fact, it is estimated that 50% of all men and 33% of all women living in the United States will develop some type of cancer in their lifetime. Therefore cancer constitutes a major public health burden and represents a significant cost in the United States. For decades, surgery, chemotherapy, and radiation were the established treatments for various cancers. Patients usually receive a combination of these treatments depending upon the type and extent of their disease. But the chemotherapy is most important option for cancer patient when the surgery treatment is impossible.
DNA alkylating agents (e.g. nitrogen mustards, platinum-based complex) were among the first chemotherapeutic agents rationally applied to the treatment of cancer. DNA alkylating agents generally exert cytotoxic activity by forming DNA adducts or crosslinks between DNA strands under conditions present in cells, directly interfering with the reproductive cycle of the cell. Mechlorethamine, an analogue of mustard gas and derived from chemical warfare research during World War II, has been used in the cancer chemotherapy for over 60 years. Other approved nitrogen mustards for cancer treatment include the Chlorambucil, Melphalan, Cyclophosphamide, Ifosfamide, Bendamustine, Estramustine, and Uramustine. Some novel nitrogen mustards, such as TH-302 and PR-104, are still in human clinical trials. Another class of widely used DNA alkylating agents is the platinum-based compounds including Cisplatin, Carboplatin, Oxaliplatin, Satraplatin, Picoplatin, Nedaplatin, Lobaplatin, and Heptaplatin (Markus Galanski, et. al., Current Medicinal Chemistry, 2005, 12, 2075-2094).
For example, the DNA alkylating agent Bendamustine, first synthesized in 1963, consists of an alkylating nitrogen mustard group and a purine-like benzimidazol moiety (Barman Balfour J A, et al, Drugs 2001, 61: 631-640). Bendamustine has been shown to have substantial activity against low-grade lymphomas (Herold M, et al., Blood, 1999, 94, Suppl 1: 262a), multiple myelomas (Poenisch W, et al., Blood 2000, 96, Suppl 1: 759a), and several solid tumors (Kollmannsberger C, et al., Anticancer Drugs 2000, 11: 535-539). It was also reported that bendamustine effectively induces apoptosis in lymphoma cells (Chow K U, et al., Haematologica, 2001, 86: 485-493). On March 2008, the FDA granted approval to market bendamustine for the treatment of chronic lymphocytic leukemia (CLL). On October 2008, the FDA granted further approval to market bendamustine for the treatment of indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Currently bendamustine is in clinical trial for a variety of cancer indications, such as leukemia, lymphoma, small cell lung cancer, multiple myeloma, MDS, ovarian cancer, breast cancer, and brain tumor.
Cisplatin is another widely used DNA alkylating agent for cancer treatment. The tumor-inhibiting properties of cisplatin were first reported in 1969 by Barnett Rosenberg four years after his pioneering work performed with the original intention of investigating the influence of an electric field on bacterial growth and 125 years after the first synthesis of cisplatin by Michele Peyrone. Today, cisplatin has become one of the most successful anticancer drugs and been used in nearly 50% of all tumor chemotherapies. Although the first-generation cisplatin has a wide spectrum of anticancer activity, it does have significant side toxicity, and its clinical use can also be limited by the existence or development of resistance. In an attempt to overcome these problems, several thousand platinum-based compounds have been synthesized and screened. Substitution of the two ammine moieties of cisplatin with the diaminocyclohexane (DACH) group led to compounds that had good antitumour activity and lack of cross-resistance with cisplatin, but which were poorly water-soluble, limiting their potential for clinical development. Further modifications aimed at improving water solubility by replacing the chloride moieties of cisplatin resulted in the discovery of oxaliplatin. (Joanne Graham et al., Nature Reviews-Drug Discovery, 2004, 3, 11-12). Oxaliplatin has a broad spectrum of anticancer activity and a better safety profile than cisplatin. It also shows a lack of cross-resistance with cisplatin or carboplatin (another widely used platinum-based compound), which is thought to result from the chemical and steric characteristics of the DACH-platinum-DNA adducts. Observations, in contrast to cisplatin and carboplatin, oxaliplatin was active against several colon cancer cell lines in the National Cancer Institute's Anticancer Drug Screen Panel provided impetus for its clinical evaluation in this indication. In 2002, Oxaliplatin became the first platinum-based anticancer drug to be approved by US FDA for the treatment of colorectal cancer, a major cause of cancer deaths worldwide.
Antimetabolites are another class of extensively used chemotherapy for cancer treatment. Antimetabolite means a substance which is structurally similar to a critical natural metabolite in a biochemical pathway leading to DNA or RNA synthesis, but acts to inhibit the completion of said biochemical pathway. More specifically, antimetabilites typically function by (1) competing with metabolites for the catalytic or regulatory site of a key enzyme in DNA or RNA synthesis, or (2) substitute for a metabolite that is normally incorporated into DNA or RNA, and thereby producing a DNA or RNA that can't support replication. Major categories of antimetabolites include (1) folic acid analogs, which are inhibitors of dihydrofolate reductase (DHFR); (2) purine analogues, which mimic the natural purines (adenine or guanine) but are structurally different so they competitively or irreversibly inhibit nuclear processing of DNA or RNA; and (3) pyrimidine analogues, which mimic the natural pyrimidines (cytosine, thymidine, and uracil) but are structurally different so they competitively or irreversibly inhibit nuclear processing of DNA of RNA. Typical antimetabolite drugs include antifolate (such as Aminopterin, Methotrexate, Pemetrexed, and Raltitrexed), Purine analogues (such as Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Pentostatin, and Thioguanine), and Pyrimidine analogues (such as Cytarabine, Decitabine, Fluorouracil, Capecitabine, Floxuridine, Gemcitabine, Enocitabine, and Sapacitabine). Some of these antimetabolites, for example, Methotrexate, Fluorouracil, and Gemcitabine, are the cornerstone of modern chemotherapy.
For example, Fluorouracil (5-FU) is an antimetabolite and has been in use as chemotherapy against cancer for about 40 years. As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis by inhibiting the cell's ability to synthesize DNA. Like many anti-cancer drugs, 5-FU's effects are felt system wide but fall most heavily upon rapidly dividing cells that make heavy use of their nucleotide synthesis machinery, such as cancer cells. Some of the principal use of 5-FU is in colorectal cancer and breast cancer, in which it has been the established form of chemotherapy for decades.
Gemcitabine is another well-known antimetabolite and chemically a nucleoside analog in which the hydrogen atoms on the 2′ carbons of deoxycytidine are replaced by fluorine atoms. As with fluorouracil and other analogues of pyrimidines, the drug replaces one of the building blocks of nucleic acids during DNA replication. The process arrests tumor growth, as new nucleosides cannot be attached to the “faulty” nucleoside, resulting in apoptosis. Gemcitabine is used in various carcinomas: non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer.
The following table shows some well known examples of DNA alkylating agents and antimetabolites drugs for cancer treatment. Although these conventional chemotherapeutic drugs have made a significant contribution to cancer treatment, the dose-limiting toxicities and drug resistance remain significant hurdles in the use of these drugs. Therefore, there is a strong need for continuous search in this field of art for the novel derivatives of these drugs with improved anti-cancer activities.
